1. Field of the Invention
The invention relates generally to methods of diagnosing and monitoring the course of a cancer, and more specifically to methods of detecting cancer cells by detecting methylation silencing of GATA-4 and/or GATA-5 gene(s), which encode transcription regulatory proteins, to methods of diagnosing a cancer in a subject by detecting such methylation silencing in a cell sample obtained from the subject, and to methods of treating a subject having a cancer by effecting expression of methylation silenced GATA-4 and/or GATA-5 in cancer cells of the subject.
2. Background Information
Cancers can occur as a result of genetic changes such as mutations of a gene, as well as epigenetic mechanisms, which are not associated with mutation of a DNA sequence. The most commonly observed epigenetic change involves silencing of gene expression due to methylation of the gene sequence, particularly the 5′ upstream gene regulatory sequences. Methylation of cytosine residues located 5′ to guanosine in CpG dinucleotides, particularly in CpG-rich regions (CpG islands), often is involved in the normal regulation of gene expression in higher eukaryotes. For example, extensive methylation of CpG islands is associated with transcriptional inactivation of selected imprinted genes, as well as the genes on the inactivated X chromosome in females. Aberrant methylation of normally unmethylated CpG islands also is present in immortalized and transformed cells, and has been associated with transcriptional inactivation of tumor suppressor genes in human cancers.
Changes to genes that are associated with cancer, including mutations that result in loss of expression of gene or in expression of a defective gene product, and epigenetic mechanisms such as methylation-silencing of gene transcription, provide markers useful for determining whether a cell is susceptible to loss of normal growth control and, therefore, potentially a cancer cell. For example, a mutation of the BRCA1 gene has been associated with breast cancer. As such, diagnostic tests can be performed using cells, for example, from a woman with a family history of breast cancer to determine whether the woman has the BRCA1 mutation that is a marker for breast cancer. The prostate specific antigen (PSA) is another example of a marker, in this case for prostate cancer. Although neither the defect resulting in expression of the PSA nor the normal function of PSA in the body is known, PSA nevertheless provides a valuable cancer marker because it allows the identification of men predisposed to prostate cancer or at a very early stage of the disease such that effective therapy can be implemented. More recently, methylation-silenced transcription of a suppressor of cytokine signaling/cytokine-inducible SH2 protein family member, the SOCS-1 gene was found to be associated with various cancers, including hepatocellular carcinoma, multiple myeloma, and acute leukemias. As such, screening assays directed to detecting the methylation status of the SOCS-1 gene can provide diagnostic information relating to such cancers.
Cancer often is a silent disease that does not present clinical signs or symptoms until the disease is well advanced. As such, the availability and use of markers that allow the identification of individuals susceptible to a cancer, or that allow detection of a cancer at an early stage, can be of great benefit. Unfortunately, such markers are not available for most cancers and, as a result, many cancer patients do not seek medical assistance until the cancer is at a stage that requires radical therapy, or is untreatable. Thus, a need exists for markers that can be used to detect cancer cells. The present invention satisfies this need and provides additional advantages.